Genomics: The Next Big Thing in Mining the Genome Women's Health: Communicating Breast Cancer Risk and Means of Prevention Oral Biology: The Mouth's Microbes Could Hold Clues to Early Cancer Detection Genetics: Rearrangement of DNA Shown to Cause Certain Lymphomas Structural Biology: Molecular Jumping Jack Shows Off Moves Minority Health: Drug Abuse and Bioterrorism Among Issues Raised by Minority Fellows The Summer Bookshelf: Recent Books by Faculty of HMS, HSDM, and HSPH Cloning Study Creates Tissues for Transplantation Heart Protection by Corticosteroids Bypasses Gene Regulation Anti-aging Mechanism Shown in Yeast, May Be Similar in People Proceedings of the HMS Faculty Council Actor Ford Named Global Environmental Citizen Portraits of HMS Women Faculty Leaders Unveiled Human Genome Chief Forecasts Blue Skies for Medical Genomics HOLLIS Gets New Look, Features Alpert Prize Winners Reveal Secrets of the Heart HMS Junior Faculty Receive Armenise Awards Biosecurity Conference Addresses Bioterrorism Threat Barger Speaker Urges Advocacy New Howard Hughes Investigators Chosen for Patient-oriented Research HMS Presents Faculty Awards Honors and Advances Where Have All the Surgeons Gone? Front Page

GENETICS Rearrangement of DNA Shown to Cause Certain Lymphomas In a report published May 29 in Cell online, HMS researchers explain the origins of certain types of B cell lymphoma. Frederick Alt, a Howard Hughes investigator and the Charles A. Janeway professor of pediatrics and genetics at Children's Hospital and the Center for Blood Research, and coworkers used a mouse model to pin down how large-scale and aberrant DNA movements lead to cancer gene amplification. The chromosomal translocations that occur in the fragile genomes of many cancer cells are associated with acquired resistance to chemotherapy and with tumor progression, but up to now it was unclear how such DNA rearrangements link to cancer. The mice used in the study lacked the tumor suppressor gene p53 and also factors that repair broken double-stranded DNA. During normal B cell development, these factors--components in the so-called nonhomologous DNA end-joining pathway--are essential for standard V(D)J recombination, the process of gene rearrangement that assembles the variable regions of the antibody genes from component V, D, and J modules to generate a fully functional immunoglobulin gene. The end-joining and p53 double-mutants succumb to pro-B cell lymphomas in which both the c-myc gene and a portion of the IgH locus are amplified. Co-lead authors Chengming Zhu, Kevin Mills, and David Ferguson characterized chromosomes and translocation junctions present in the mouse pro-B cells that had undergone translocation and went on to produce tumors. These tumors routinely contained two types of translocation resulting from an unmended double-strand break in the IgH gene on chromosome 12 of mutant mice. One was a simple translocation of the centromeric portion of chromosome 12 to the distant portion of chromosome 15. However, these tumors also contained a second, amplified translocation junction oriented such that the centromeric portion of chromosome 12 was fused to the centromeric portion of chromosome 15 containing the c-myc gene. The structure of the amplified junction suggested that the gene amplification process occurred through well-characterized breakage-fusion-bridge cycles employing dicentric chromosomes, as first described in 1941 by Barbara McClintock. In support of this, the researchers identified rare amplification intermediates and end products predicted by the model. Gene amplification was first discovered by Alt more than two decades ago as a mechanism of anticancer drug resistance. Said Alt: "It was particularly satisfying that our current work on antibody gene assembly has led to new insights into the mechanism of oncogene amplification in tumors." The research is a vivid illustration of how two independent lines of investigation into basic problems such as antibody diversity and the mechanisms that underlie the nature of genomic instability can help explain the origins of cancer. --Anne Mahon